Bone formation and degradation are tightly regulated by growth factor signaling between osteoblasts that are responsible for bone formation and osteoclasts that are responsible for bone re-absorption. Coupling bone formation by osteoblasts with degradation by osteoclasts has recently become a topic of intense study; with the list of growth factors identified as coupling factors expanding. Coupling bone formation with bone re-absorption requires the recruitment of osteoblasts and osteoclasts in parallel with the recruitment of their respective progenitor cells. Osteoblasts derive from mesenchymal stem cell (MSC) while osteoclasts derive from monocytes that are a part of the myeloid-lineage; however, it remains unknown how MSC or monocytes migrate from their niche in the bone marrow to sites of new bone formation. The current understanding of the spatial and temporal regulation of osteogenesis proposes that MSC migrate from their bone marrow niche to the endosteal surface; where the MSC differentiate into osteoblasts that produce new bone. In parallel, monocytes also migrate from their bone marrow niche to the endosteal surface; where they subsequently differentiate into osteoclasts that re-absorb bone. Growth factors known to regulate bone formation include TGFβ-, BMP- and the canonical Wnt-ligands. While osteoclast formation from monocyte precursors and bone re-absorption are regulated through the expression of MSCF, OPG and RANK-ligand. In parallel, osteoclast activity is also regulated by the expression of the TGFβ-, BMP- and the non-canonical Wnt-ligands. However, many developmental growth factors involved in tissue patterning, including TGFβ-, BMP- and the Wnt-ligands, promote bone formation and re-absorption. The maintenance of healthy bone requires constant remodeling, in which bone is made and destroyed continuously. The netrin-, RGM- and slit-ligands were identified as growth factors that could potentially couple bone formation and re-absorption through the regulation of progenitor cell differentiation within the 3-dimensional structure of bone.
The introduction of an implant into bone results in a biochemical cascade that results in a pro-inflammatory response that is partially mediated by macrophages, which are derived from the myeloid lineage and can contribute to the degradation of bone or an implant material. Currently implants and implant materials are chosen to minimize the macrophage response while being optimally osteo-conductive and promoting maximum bone-implant integration. Alternatively, the introduction of autograph with an implant or the use of devitalized bone tissue graft has been employed in concert with the material properties of an implant as a means of increasing osteo-integration; however, these approaches have often been problematic. Ideally, materials could be designed to be both self-organizing and self-assembling.
Generating bone as an adjuvant therapeutic approach employed during orthopedic trauma procedures or during routine spine fusion procedures represents a continuing challenge in orthopedic surgery. Specifically, these adjuvant bone-generating therapies seek to increase the growth of healthy bone at the site of surgical intervention in parallel with decreasing the healing time for bone. In the last several decades a number of attempts have been made to use various growth factors with osteogenic potential, including BMP. Unfortunately, BMP based therapies intended to generate bone also carry a risk for tumorigenesis in patients who may be undergoing X-radiation therapy or possess nascent undetected tumor. Further, BMP based therapies cannot be used in patients with active tumor, which is particularly unfortunate since these patients would benefit significantly from therapies that increase bone formation during surgical intervention.
Impaired fracture healing continues to present a significant challenge in orthopedic surgery and bone healing. Fracture non-union rates as high as 5-20% have been reported. The morbidity and cost associated with the treatment of patients developing non-unions can be substantial. Approximately 10% of the 6.2-million fractures encountered each year have difficulty healing. Various options exist to help accelerate bone healing, with unproven efficacy. Iliac crest bone graft is still considered to be the gold standard but has significant issues related to harvest site co-morbidity. Growth factor based therapies that include platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and parathyroid hormone (PTH) has shown initial success in cell culture studies; however, their efficacy remains unproven in clinical application. An additional option, such as bone morphogenic protein-2 (BMP2) and BMP7, has been shown to have success in accelerating fracture healing with diaphyseal fractures. However, there are risks associated with the use of BMP that include increased infection, increased risk of tumor growth, and an increased risk of local osteolysis. Many of the risks associated with treatments that include BMP also preclude the use of BMP for patients with other pathologies.
The therapeutic ability to increase bone formation, as an adjuvant during orthopedic surgery, while not increasing the potential for tumor growth is currently a limitation of commercially available biologics, in treating complex orthopedic problems such as spine fusion, fracture healing and the management of fracture non-unions.
In the field of orthopedic trauma, particularly with open fractures with large defects and non-unions; autogenous/allogenic bone grafts are the primary treatment options. However, autogenous harvested bone graft, used as the gold standard to achieve bone formation, has risks of infection and donor site pain. Other allogenic bone graft substitutes have not shown similar efficacy when used singularly. The same limitations exist for spine surgery when these are used during fusions.
Cortical and cancellous bone derived from cadaveric sources serves to fill space and are primarily osteo-conductive without significant osteo-inductive potential. Hence, biologics such as PDGF, VEGF and BMP are used to increase rates of healing or fusion, and their application adds to the cost of treatment. However, these biologic therapies stimulate proliferation during development in a range of cell phenotypes, which presents an inherent and unacceptable oncologic risk.
De-mineralized bone matrix and calcium phosphate substitutes have not shown high efficacy at accelerated bone healing and also have significant cost associated with them due to production costs.
Recombinant BMP2 (rhBMP2) is a implant commercially developed by Medtronic known as Infuse that is distributed in small (4.2-mg of BMP2 with 2× collagen sponges for a 15-mg/cm3 implant), medium (8.4-mg of BMP2 with 4× collagen sponges for a 15-mg/cm3 implant), large (12-mg of BMP2 with 6× collagen sponges for a 15-mg/cm3 implant) and large-II (12-mg of BMP2 with 1× collagen sponge for a 15-mg/cm3 implant). All sizes of the Infuse implant are approved for spine and maxillofacial applications while only the large-II implant is approved for fracture. Infuse is administered by reconstituting the powdered BMP2 with sterile saline and then adding the BMP2-saline solution to the collagen sponge; after which the implant is delivered locally during surgical intervention.
Recombinant BMP7 (rhBMP7 or OP1) is an implant commercially developed by Sryker and now owned by Olympus known as OP1. OP1 is distributed as OP1-putty (20-mL vial containing powdered bovine cartilage and 3.3-mg of BMP7) or OP1-implant (1-g of powdered bovine cartilage and 3.3-mg of BMP7). The OP1-putty is approved for spine fusion surgeries while the OP1-implant is approved for treating fractures and fracture non-union surgery. OP1-putty or the OP1-implant is administered by reconstituting the powdered BMP7 with sterile saline and then adding the BMP7-saline solution to the collagen implant; after which the implant is delivered locally during surgical intervention.
Recent observations during neuro-development have identified a family of loosely related proteins and receptors that possess attractive and repulsive properties. The netrin-ligands are a class of four secreted (netrin-1, netrin-3, netrin-4 and netrin-5) that binds the DCC-, neogenin- and UNC5A-D receptors. The repulsive guidance molecules (RGMa and RGMb) are ligands that bind the neogenin-receptor and have been identified to antagonize netrin-ligand signaling. Netrin-ligands were initially identified in mammals as essential for commissural axon migration and may posses the ability to regulate attractive migration in bone. The slit-ligands (slit1, slit2 and slit3) and their roundabout receptor (ROBO1, ROBO2, ROBO3 and ROBO4) possess the ability to regulate repulsive cell migration in bone, since the slit-ROBO signaling axis has been shown to regulate neurite repulsive migration in the brain.
The netrin-ligands possess laminin-binding sites that act to sequester the netrin-ligand proteins in a collagen matrix and are considered an important regulatory element of netrin-ligand function. The slit-ligands have been shown to bind heparan sulfate and the interaction between heparan sulfate and the slit-ligand is required for slit-ligand function; whereas, collagen bound heparan is important in sequestering the slit-ligands.